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Read Now: Expert Opinions on HIV Cure Research
IDSA 2007: San Diego, California; October 4-7, 2007

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The Body Covers: The 45th Annual Meeting of the Infectious Diseases Society of America
IDSA 2007: New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access

October 10, 2007

This is part two of a two-part article. For part one, Challenges of Current Antiretroviral Therapy, click here.


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Eric Daar is the chief of the Division of HIV Medicine at Harbor-UCLA Medical Center, and a professor of medicine at the David Geffen School of Medicine at UCLA.


New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access

TITAN, a Detailed Analysis

In addition to learning how to best deal with some of the adverse effects associated with current therapy, we also need to think about how to manage patients who are experiencing virologic rebound and the emergence of resistance. There were several studies presented at this meeting that deal specifically with the treatment-experienced patient, both with existing drugs and newer drugs. The first of those that I'll talk about was one using existing drugs -- the TITAN trial. It was a head-to-head comparison in treatment-experienced patients who were lopinavir/ritonavir-naive who received darunavir [TMC114, Prezista]/ritonavir [RTV, Norvir] with an optimized background versus lopinavir/ritonavir with an optimized background.

The original data was presented7 and published8 over the summer. These patients were followed for 48 weeks for the primary outcome. The patient population that was enrolled consisted of people who were treatment-experienced, but were lopinavir/ritonavir-naive. Resistance testing was not performed routinely at baseline, although now all of the baseline resistance data is available.

Click to enlarge.They stratified [the data] based on viral loads of above and below 100,000, and the use of NNRTIs. The baseline characteristics, in reviewing this, demonstrated a few things that I think are important. One of which was that about 20% of the people were actually not on treatment at the time of enrollment. They were in the midst of a treatment interruption, for any one of a number of reasons. About 30% of them were actually PI-naive.

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The other big imbalance between the two groups was that when the researchers ultimately did get resistance data, it proved that there was a larger number of people resistant to their assigned PI in the lopinavir/ritonavir arm (about 10%) versus the darunavir/ritonavir arm (about 2%).

The overall outcome of this study was that the researchers were able to show that the darunavir/ritonavir arm was both non-inferior, as well as superior, to lopinavir/ritonavir, for the overall population.

In the original analysis, they broke this down to try to better define how the imbalance in baseline resistance may have influenced the outcome. They found that even if you focused [only] on patients who had evidence of phenotypic susceptibility to lopinavir/ritonavir -- meaning less than 10-fold -- you still saw that for patients who had a virologic response of less than 50 copies/mL, darunavir/ritonavir was non-inferior. It didn't quite meet superiority when you broke it down that way.

Click to enlarge.Here at IDSA 2007, David Hardy presented a more detailed analysis looking at baseline characteristics and how that influenced outcome.9 This included a variety of univariate and multivariate analyses that incorporated many factors that included things like: baseline viral load and CD4, the number of active drugs in the optimized background, the level of PI resistance with prior PI experience.

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In addition, for PI resistance, they broke it down, both based on those who had less than a 10-fold resistance to lopinavir/ritonavir at baseline, as well as the number of mutations from the International AIDS Society-USA profile.

What they found, in the multivariate analysis, was that the difference in response favoring darunavir/ritonavir was maintained even after adjusting for all of these various factors. They also found that when you broke it down based on the subset of patients who were susceptible to lopinavir/ritonavir (based on the phenotype being less than 10-fold), that in that population, as you accumulated more International AIDS Society-USA protease mutations, you actually saw an attenuation of the response.

Click to enlarge.I think that this further analysis reinforces the observations that darunavir/ritonavir in this patient population is highly effective. While there were some imbalances in the baseline characteristics -- even when accounting for many of these things -- darunavir/ritonavir appears to, at a minimum, be non-inferior to lopinavir/ritonavir, and may be trending towards better, with less virologic failures and less accrual of additional mutations. So it appears to be a very viable option for patients like this, and certainly for patients who are darunavir/ritonavir-naive.

Enfuvirtide in Highly Treatment-Experienced Patients

As we move from those patients who have an intermediate level of resistance to patients who have more advanced resistance, there were several presentations looking at existing drugs and how they complement newer drugs, and then more details on some of the newer drugs and how they may fit into managing this population.

There was a poster presented that summarized the data regarding the utility of enfuvirtide [T-20, Fuzeon] as a new agent from a variety of trials in highly treatment-experienced patients.10 Many of these studies have included that type of an analysis. Here, they looked at all of these studies and put them together in a single presentation.

Click to enlarge.The studies of interest that they looked at go back to: the RESIST trial,11 with tipranavir [TPV, Aptivus]; the POWER trials,12,13 with darunavir/ritonavir; the more recent MOTIVATE 114 and 215 trials, with maraviroc [MVC, Selzentry, Celsentri], a CCR5 antagonist; the BENCHMRK 116 and 217 trials, with raltegravir [MK-0518], an integrase inhibitor; as well as the phase 2B study with elvitegravir [GS 9137, JTK-303]18; and the recent DUET 1 and 219 studies, with etravirine.

The researchers broke the analysis down for each of these different studies, based on patients who received enfuvirtide versus those who didn't.10 For the most part, they were really able to demonstrate, in this particular analysis, that enfuvirtide, particularly in people who have not been on enfuvirtide in the past, results in additional virologic suppression over the newer drug, whether it was a new protease inhibitor or a CCR5 antagonist, integrase, or NNRTI, in most of these trials.

The one [set of studies] in which it was most difficult to really demonstrate a difference -- although there was some increase, but it was modest -- was in the DUET 1 and DUET 2 trials.19 The addition of enfuvirtide in this situation didn't seem to markedly increase the virologic response.

We'll be talking about a more detailed analysis of DUET 1 and DUET 2 in a moment, but the explanation for this most likely relates to the fact that DUET 1 and 2 were unique, and that everybody in the intervention arm received a new drug, in this case etravirine, a second-generation NNRTI, for which many of them were likely to be susceptible. But they also all had darunavir/ritonavir as part of their optimized background regimen, with about 95% of them being darunavir/ritonavir-naive. We know from the POWER trials and the TITAN trial I just discussed that many of these people will have a virologic response.

So, in the DUET trials -- unlike some of the others where there was one new drug added, most people receive one new drug -- the people in the intervention arm received two new drugs: darunavir and the new NNRTI. It may be that adding a third active drug, in this case enfuvirtide, is going to have a smaller incremental increase in the level of viral suppression.

I think the take home from this type of data, and others, is that enfuvirtide continues to play a key role in the management of highly treatment-experienced patients, particularly if you need a second or perhaps third fully active drug in the regimen.

It also illustrates, in a variety of analyses, the importance of thinking about enfuvirtide based on whether the person has been on it in the past, because we know from studies that enfuvirtide resistance can occur quite quickly.20 In all likelihood, if somebody's been on enfuvirtide with ongoing viremia, they are probably going to be resistant to it. That explains why, when they do these analyses with everybody on T-20, you don't see as much of an effect as when you focus on the people who are T-20-naive, where they are more likely to have susceptible virus.

DUET Efficacy

There were two presentations looking at further analyses from the DUET 1 and 2 trials. These are important studies. They are going to guide treatment with the new drug etravirine (the new NNRTI that's available on expanded access and likely to get approved in the coming months), and they may also provide some additional insight on how to manage these patients who are highly treatment-experienced in the future.

The DUET 1 and 2 trials were, again, two almost identical trials, carried out in different parts of the world, of highly treatment-experienced patients.19 They all had to have evidence of NNRTI resistance, documented either at the time they came into the study for screening or in the past on a documented, genotypic test. So they had to have proof that they actually had NNRTI resistance.

They came into the trial -- almost 1,200 of them -- and they got randomly assigned to receive an optimized background, which in all cases included darunavir/ritonavir, alone with placebo (importantly) versus etravirine, the new NNRTI. I think it is important, when we start talking about things like safety, to recognize that this was a placebo-controlled trial, which allows us to do that. The other important characteristic about this study that really did make it different than all of the others in highly treatment-experienced patients is the use of darunavir/ritonavir in a population of patients that, for the most part (about 95%), were darunavir/ritonavir-naive. So the optimized background, in this case, almost always included probably one fully active drug. Then we were adding to that. It sometimes included even more than that.

Patient baseline characteristics: The viral load was approaching 100,000, and the CD4 count median was about 100. When you looked at the patients in the study, about half of them received enfuvirtide. About 25% were actually enfuvirtide-naive.

Click to enlarge.In the primary analysis, using this time to loss of virologic response [TLOVR] for less than 50 copies/mL, it was 59% versus 41%, which was highly significantly different. Similarly, the level of viral suppression in the group that received etravirine was about 2.4 logs versus 1.7 logs in the control group -- which was highly significantly different. But notably, both groups did very well, including the placebo group, with regards to viral suppression and proportion undetectable.

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Actually, the placebo group ended up with numbers that looked quite similar to those of the POWER12,13 trials since, indeed, those are the people who were in POWER -- highly treatment-experienced patients in the intervention arm who received darunavir and ritonavir.

The mean change in CD4 count favored the etravirine group: an 86-cell increase versus 67 cells.21 When they broke it down based upon whether patients received new T-20 or not, as I mentioned before, there was a better response in those who received the etravirine with T-20 for the first time, than those who received T-20 for the first time without etravirine. It was 67% versus 62%. But the difference was not significant and, in all likelihood, this is a hint that [the benefit of] having two fully active drugs, such as darunavir/ritonavir and etravirine, isn't improved dramatically by the addition of a third active drug. This might provide some insight as to how many active drugs we need in these highly treatment-experienced patients, or what the incremental gain of adding a third, or a fourth, active drug is.

In fact, they further looked at this analysis based upon the phenotypic susceptibility score in those who had an optimized background regimen that had no active drug -- so they were even resistant to darunavir/ritonavir. The response rate, at less than 50 copies/mL, was only 8%, versus in those who received etravirine, where it was 45%.

Click to enlarge.Similarly, there was a difference in patients who had one active drug in the optimized background: 60% with etravirine, 30% with placebo. But when you had greater than or equal to two active drugs in the background, the difference was modest, at 74% versus 67%. So, again, this recurring theme.

What was commented on, and has been described in previous analyses, is that since this is a new drug in an existing class, there's going to be some level of cross-resistance in people who are NNRTI-experienced. In analyses from the data from DUET 1 and 2, they identified 13 key mutations that were associated with an attenuated response to therapy.

Click to enlarge.Interestingly, this did not include the K103N mutation since this drug was developed to have activity against the K103N-containing virus. They found -- as has been described before -- that there's a decrease in the response rate overall of the proportion of people who experienced a viral load drop to less than 50 based upon the number of etravirine-associated resistance mutations. If you had no etravirine-associated mutations, the response rate was about 75%. If there was one, it was 60%, and two, 58%. It was really only when you got to three that you saw a substantial drop-off, down to about 41%.

Click to enlarge.The observation that's been made before, and was described here, is that it turns out that, even in the placebo group, there was a relationship between the number of etravirine-associated mutations and response rate, with somewhat of a drop-off when you get to two or three mutations, suggesting that this is probably not just a marker for reduced response to etravirine, but may also be a marker for the extent of overall resistance within the regimen, since it influenced both groups.

Click to enlarge.I think, overall, it's very clear that this is going to be a very active new drug for highly treatment-experienced patients who have less than three of these etravirine-associated mutations, and that there is a hint from this study that there may not be a lot of additional gain by adding a third fully active drug to a regimen that already includes two fully active drugs, with other drugs in the background, such as nucleoside reverse transcriptase inhibitors [NRTIs].

DUET Safety Data

In addition to defining the efficacy of these new drugs, it is also important to completely understand the issues surrounding the safety of new drugs. I think one of the concerns with new drugs in existing classes is the level of overlapping toxicity that may exist. Since etravirine is an NNRTI, there are concerns about whether there would be overlapping toxicity -- such as rash, transaminase abnormalities and neuropsychiatric complications -- with existing NNRTIs.

At this meeting they presented a pooled analysis of the DUET 1 and 2 trials' safety and tolerability at 24 weeks. They were able to do this because this was, indeed, a placebo-controlled set of trials.22 So you could really define the differences in select adverse events between patients who received the etravirine with an optimized background, versus those who received the optimized background alone. Again, recognizing that everybody in both groups received darunavir/ritonavir.

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One of the most notable things about the baseline characteristics is that about 40% of the patients admitted to having some type of neuropsychiatric problems in the past. About 10% had a history of an NNRTI-related rash. Now, presumably, these weren't hypersensitivity type rashes, but the patients did, indeed, have a rash coming into these studies.

If you looked at overall grade 3, 4 adverse events, there was really no difference overall between the arms. But when you looked at rash, there was indeed a higher frequency of rash amongst those who received etravirine: 17%, versus 9% in the control group, which was highly significant.

The researchers further characterized this. They described that there was only 1.3% of patients who had a grade 3 or 4 rash in the etravirine group, versus none in the placebo group. In the onset: the median time was about 12 days. The duration was about 11 days. Only 2.2% of the population had to discontinue because of rash. So it seems like the rash that exists occurs at a relatively low frequency, even in this highly treatment-experienced population. It generally is mild and only results in discontinuation in select cases. They said there were no constitutional symptoms, or systemic symptoms, associated with it, or any mucous membrane involvement suggestive of a Stevens-Johnson type syndrome.

Click to enlarge.Further, looking at the breakdown, they found that there was a somewhat higher frequency of rash amongst women than men, and they found in other potential complications or adverse events that there was really no difference with regards to central nervous system toxicities, psychiatric adverse events, or grade 3, 4 LFT [liver function test] abnormalities.

Click to enlarge.Similarly, there was no apparent difference in the levels of lipids over time between the two groups of patients. One observation where there was a significant difference was with regards to a higher rate of hospitalizations amongst those who received placebo versus etravirine: 16% versus 11%. This was significant, although the details about what these hospitalizations were for were not available at the time of this presentation.

Click to enlarge.Again, it's nice to collect additional safety data from a large number of people in a placebo-controlled trial with a drug that we're going to start using in clinical practice. This starts to get at the concern that some have about whether they can use this in people who have had a non-hypersensitivity type rash with other NNRTIs. It certainly appears to be a promising result.

Maraviroc

We'll close this review with a presentation that was a late breaker. I think everybody is familiar with maraviroc, a new CCR5 antagonist that was recently approved by the FDA [U.S. Food and Drug Administration] for patients who have R5-only virus, meaning at the time of screening, using a tropism assay, they didn't have any detectable CXCR4-utilizing viruses.

One of the concerns about using this drug is the potential for selecting for CXCR4-utilizing viruses, and what the consequences of that might be, since there's natural history data suggesting an association between the presence of these viruses and CD4 decline in clinical progression.

There have been detailed analyses of patients treated with CCR5 antagonists who experience the emergence of this viral population and who have not shown any suggestion of CD4 declines, at least at 24 and 48 weeks.

Another study that was presented several months ago, at 24 weeks, was a study designed in part to address the issue of what would happen if you treated people who had CXCR4-utilizing virus.23 This was the maraviroc study 1029, which took the individuals who would not have been eligible for the MOTIVATE trials because they had evidence of either dual/mixed-tropic virus or X4 virus, or [they were part of the] small number [for whom] the virus was simply not able to be typed by the assay. These patients were offered enrollment in this study.

Click to enlarge.This was a randomized, controlled trial of an optimized background with maraviroc, either once a day or twice a day, versus placebo. It included about 50 to 60 people in each arm, so it was a relatively small study to address both limited efficacy data and safety, to see whether enriching for a population of dual/mixed-tropic or X4 viruses would be associated with worse outcomes.

Click to enlarge.They followed these patients for 24 weeks, and although they had previously reported that data, I think it's really important that we have more long-term follow-up, particularly from a safety perspective. This was the 48-week data from this population of patients who came into the study with a median CD4 count of about 40 and a viral load of about 100,000.24 About half of them received enfuvirtide, and less than two active drugs were present within these regimens for about 50% of the patients.

Click to enlarge.The investigators looked at the virologic change and they found that the difference in viral load suppression was essentially no different across the three different arms, consistent with what had been previously seen. When you looked at the proportion that got to less than 400 and less than 50 -- again, small numbers -- there was no significant difference between the groups.

Click to enlarge.It's based on this kind of data that most people believe that patients who have dual/mixed-tropic or X4 virus at baseline are not likely to derive virologic benefit from this drug, recognizing that the sample size is quite small. But [it, along with data from the big MOTIVATE trials, is] also why the current recommendations are that we'll be using this drug in treatment-experienced patients who don't have evidence of dual/mixed-tropic virus identified on a screening assay.

They reported the 48-week data on change in CD4 count, and, just as they had seen before, while we were worried that enriching for this population may be associated with CD4 decline and disease progression, it actually was associated with a better CD4 increase than what was seen in the placebo group. The reason for this isn't known yet, but there's a lot of speculation and I know there's some work going on to try to better define what is the effect of adding a CCR5 antagonist on select CD4 cell populations.

Click to enlarge.Adverse events were looked at carefully in this study, and there were no differences between the groups. There were no significant differences in the number of category C events. Previous studies with another CCR5 antagonist, vicriviroc [SCH 417690, SCH-D], raised some issues about the potential association with the emergence of malignancies. This has not been supported by further analysis from those trials, and certainly not from analysis of the MOTIVATE trials, nor this one.

Click to enlarge.Overall, there were about two malignancies in each of the three different groups, but no Hodgkin's lymphomas, no Kaposi's sarcomas. In general, it doesn't seem that there are any ill effects on CD4 counts or clinical progression after 48 weeks.

Adverse events: There was this continued increase in cough that was seen somewhat in the maraviroc groups, but no obvious evidence of increased things like pneumonia. There was no evidence of problems with transaminases, which came out of one of the earlier trials with CCR5 antagonists.

Click to enlarge.I think, in general, the 48-week data is completely consistent with the 24-week data and provides further reassurance that enriching for a population of dual/mixed-tropic virus won't be associated with a poor outcome in patients treated with CCR5 antagonists.


Conclusion

This is almost the last of a series of extremely important meetings that occurred during the course of this year. What's emerged is really unprecedented in the field -- with so much new data on how to optimally utilize existing drugs. But even more importantly, we've recently seen so much new data on how to better manage treatment-experienced patients with the emergence of several new drugs in new classes, as well as new drugs in existing classes. All of this has already had, and will certainly continue to have, a dramatic impact on the care of highly treatment-experienced patients.

I think that we're looking forward to an extremely exciting six months, as many of these new drugs reach the clinic and as more data emerge in the coming year, starting with the retrovirus conference in Boston in 2008.

This is part two of a two-part article. For part one, Challenges of Current Antiretroviral Therapy, click here.



  
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